The predictive values of monocyte-lymphocyte ratio in postoperative acute kidney injury and prognosis of patients with Stanford type A aortic dissection.

Objectives: Postoperative acute kidney injury (pAKI) is a serious complication of Stanford type A aortic dissection (TAAD) surgery, which is significantly associated with the inflammatory response. This study aimed to explore the relationship between blood count-derived inflammatory markers (BCDIMs) and pAKI and to construct a predictive model for pAKI. Methods: Patients who underwent TAAD surgery were obtained from our center and the Medical Information Mart for Intensive Care (MIMIC)-IV database. The differences in preoperative BCDIMs and clinical outcomes of patients with and without pAKI were analyzed. Logistic regression was used to construct predictive models based on preoperative BCDIMs or white cell counts (WCCs). The performance of the BCDIMs and WCCs models was evaluated and compared using the receiver operating characteristic (ROC) curve, area under the ROC curve (AUC), Hosmer-Lemeshow test, calibration plot, net reclassification index (NRI), integrated discrimination improvement index (IDI), and decision curve analysis (DCA). The Kaplan-Meier curves were applied to compare the survival rate between different groups. Results: The overall incidence of pAKI in patients who underwent TAAD surgery from our center was 48.63% (124/255). The presence of pAKI was associated with longer ventilation time, higher incidence of cerebral complications and postoperative hepatic dysfunction, and higher in-hospital mortality. The results of the logistic regression indicated that the monocyte-lymphocyte ratio (MLR) was an independent risk factor for pAKI. The BCDIMs model had good discriminating ability, predictive ability, and clinical utility. In addition, the performance of the BCDIMs model was significantly better than that of the WCCs model. Analysis of data from the MIMIC-IV database validated that MLR was an independent risk factor for pAKI and had predictive value for pAKI. Finally, data from the MIMIC-IV database demonstrated that patients with a high MLR had a significantly poor 28-day survival rate when compared to patients with a low MLR. Conclusion: Our study suggested that the MLR is an independent risk factor for pAKI. A predictive model based on BCDIMs had good discriminating ability, predictive ability, and clinical utility. Moreover, the performance of the BCDIMs model was significantly better than that of the WCCs model. Finally, a high MLR was significantly associated with poor short-term survival of patients who underwent TAAD surgery.

The prognosis of patients with postoperative hyperglycemia after Stanford type A aortic dissection surgery and construction of prediction model for postoperative hyperglycemia.

Objective: The mortality of type A aortic dissection (TAAD) is extremely high. The effect of postoperative hyperglycemia (PHG) on the prognosis of TAAD surgery is unclear. This study aims to investigate the prognosis of patients with PHG after TAAD surgery and construct prediction model for PHG. Methods: Patients underwent TAAD surgery from January 2016 to December 2020 in Xiangya Hospital were collected. A total of 203 patients were included and patients were divided into non PHG group and PHG group. The occurrence of postoperative delirium, cardiac complications, spinal cord complication, cerebral complications, acute kidney injury (AKI), hepatic dysfunction, hypoxemia, and in-hospital mortality were compared between two groups. Data from MIMIC-IV database were further applied to validate the relationship between PHG and clinical outcomes. The prediction model for PHG was then constructed using Extreme Gradient Boosting (XGBoost) analysis. The predictive value of selected features was further validated using patient data from MIMIC-IV database. Finally, the 28-days survival rate of patient with PHG was analyzed using data from MIMIC-IV database. Results: There were 86 patients developed PHG. The incidences of postoperative AKI, hepatic dysfunction, and in-hospital mortality were significant higher in PHG group. The ventilation time after surgery was significant longer in PHG group. Data from MIMIC-IV database validated these results. Neutrophil, platelet, lactic acid, weight, and lymphocyte were selected as features for prediction model. The values of AUC in training and testing set were 0.8697 and 0.8286 respectively. Then, five features were applied to construct another prediction model using data from MIMIC-IV database and the value of AUC in the new model was 0.8185. Finally, 28-days survival rate of patients with PHG was significantly lower and PHG was an independent risk factor for 28-days mortality after TAAD surgery. Conclusion: PHG was significantly associated with the occurrence of AKI, hepatic dysfunction, increased ventilation time, and in-hospital mortality after TAAD surgery. The feature combination of neutrophil, platelet, lactic acid, weight, and lymphocyte could effectively predict PHG. The 28-days survival rate of patients with PHG was significantly lower. Moreover, PHG was an independent risk factor for 28-days mortality after TAAD surgery.

Identification of immune-related hub genes and analysis of infiltrated immune cells of idiopathic pulmonary artery hypertension.

Objectives: Idiopathic pulmonary artery hypertension (IPAH) is a rare but life-threaten disease. However, the mechanism underlying IPAH is unclear. In this study, underlying mechanism, infiltration of immune cells, and immune-related hub genes of IPAH were analyzed via bioinformatics. Methods: GSE15197, GSE48149, GSE113439, and GSE117261 were merged as lung dataset. Weighted gene correlation network analysis (WGCNA) was used to construct the co-expression gene networks of IPAH. Gene Ontology and pathway enrichment analysis were performed using DAVID, gene set enrichment analysis (GSEA), and gene set variation analysis (GSVA). Infiltration of immune cells in lung samples was analyzed using CIBERSORT. GSE22356 and GSE33463 were merged as peripheral blood mononuclear cells (PBMCs) dataset. Immune-related differentially expressed genes (IRDEGs) of lung and PBMCs dataset were analyzed. Based on the intersection between two sets of IRDEGs, hub genes were screened using machine learning algorithms and validated by RT-qPCR. Finally, competing endogenous RNA (ceRNA) networks of hub genes were constructed. Results: The gray module was the most relevant module and genes in the module enriched in terms like inflammatory and immune responses. The results of GSEA and GSVA indicated that increasement in cytosolic calcium ion, and metabolism dysregulation play important roles in IPAH. The proportions of T cells CD4 memory resting and macrophage M1 were significantly greater in IPAH group, while the proportions of monocytes and neutrophils were significantly lower in IPAH group. IRDEGs of two datasets were analyzed and the intersection between two set of IRDEGs were identified as candidate hub genes. Predictive models for IPAH were constructed using data from PBMCs dataset with candidate hub genes as potential features via LASSO regression and XGBoost algorithm, respectively. CXCL10 and VIPR1 were identified as hub genes and ceRNA networks of CXCL10 was constructed. Conclusion: Inflammatory response, increasement in cytosolic calcium ion, and metabolism dysregulation play important roles in IPAH. T cells CD4 memory resting and macrophage M1 were significantly infiltrated in lung samples from patients with IPAH. IRDEGs of lung dataset and PBMCs dataset were analyzed, and CXCL10 and VIPR1 were identified as hub genes.

Unique DUOX2+ACE2+ small cholangiocytes are pathogenic targets for primary biliary cholangitis.

Cholangiocytes play a crucial role in bile formation. Cholangiocyte injury causes cholestasis, including primary biliary cholangitis (PBC). However, the etiology of PBC remains unclear despite being characterized as an autoimmune disease. Using single-cell RNA sequencing (scRNA-seq), fluorescence-activated-cell-sorting, multiplex immunofluorescence (IF) and RNAscope analyses, we identified unique DUOX2+ACE2+ small cholangiocytes in human and mouse livers. Their selective decrease in PBC patients was associated with the severity of disease. Moreover, proteomics, scRNA-seq, and qPCR analyses indicated that polymeric immunoglobulin receptor (pIgR) was highly expressed in DUOX2+ACE2+ cholangiocytes. Serum anti-pIgR autoantibody levels were significantly increased in PBC patients, regardless of positive and negative AMA-M2. Spatial transcriptomics and multiplex IF revealed that CD27+ memory B and plasma cells accumulated in the hepatic portal tracts of PBC patients. Collectively, DUOX2+ACE2+ small cholangiocytes are pathogenic targets in PBC, and preservation of DUOX2+ACE2+ cholangiocytes and targeting anti-pIgR autoantibodies may be valuable strategies for therapeutic interventions in PBC.

Analysis of infiltrated immune cells in left atriums from patients with atrial fibrillation and identification of circRNA biomarkers for postoperative atrial fibrillation.

Background: Atrial fibrillation (AF) increases the risk of stroke and heart failure. Postoperative AF (POAF) increases the risk of mortality after cardiac surgery. This study aims to explore mechanisms underlying AF, analyze infiltration of immune cells in left atrium (LA) from patients with AF, and identify potential circular RNA (circRNA) biomarkers for POAF. Methods: Raw data of GSE797689, GSE115574, and GSE97455 were downloaded and processed. AF-related gene co-expression network was constructed using weighted gene correlation network analysis and enrichment analysis of genes in relevant module was conducted. Gene set enrichment analysis (GSEA) and gene set variation analysis (GSVA) were applied to investigate pathways significantly enriched in AF group. Infiltration of immune cells was analyzed using single-sample GSEA. Differentially expressed genes (DEGs) between patients with or without AF were identified and competing endogenous RNA (ceRNA) networks of DEGs were constructed. To screen biomarkers for POAF, differentially expressed circRNAs (DEcircRNAs) between patients with or without POAF were identified. Intersection between DEcircRNAs and circRNAs in ceRNA networks of DEGs were extracted and circRNAs in the intersection were further screened using support vector machine, random forest, and neural network to identify biomarkers for POAF. Results: Three modules were found to be relevant with AF and enrichment analysis indicated that genes in these modules were enriched in synthesis of extracellular matrix and inflammatory response. The results of GSEA and GSVA suggested that inflammatory response-related pathways were significantly enriched in AF group. Immune cells like macrophages, mast cells, and neutrophils were significantly infiltrated in LA tissues from patients with AF. The expression levels of immune genes such as CHGB, HLA-DRA, LYZ, IGKV1-17 and TYROBP were significantly upregulated in patients with AF, which were correlated with infiltration of immune cells. ceRNA networks of DEGs were constructed and has_circ_0006314 and hsa_circ_0055387 were found to have potential predictive values for POAF. Conclusion: Synthesis of extracellular matrix and inflammatory response were main processes involved in development and progression of AF. Infiltration of immune cells was significantly different between patients with or without AF. Has_circ_0006314 and hsa_circ_0055387 were found to have potential predictive values for POAF.

Identification of biomarkers and analysis of infiltrated immune cells in stable and ruptured abdominal aortic aneurysms.

Objectives: The mortality rate of abdominal aortic aneurysm (AAA) is extremely high in the older population. This study aimed to identify potential biomarkers of AAA and aortic rupture and analyze infiltration of immune cells in stable and ruptured AAA samples. Methods: Raw data of GSE47472, GSE57691, and GSE98278 were downloaded. After data processing, the co-expression gene networks were constructed. Gene Ontology and pathway enrichment analysis of AAA- and aortic rupture-related gene modules were conducted using the Database for Annotation, Visualization, and Integrated Discovery. Gene set enrichment analysis (GSEA) and gene set variation analysis (GSVA) were used for further enrichment analysis. The CIBERSORT tool was used to analyze the relative abundance of immune cells in samples. Differentially expressed immune-related genes were analyzed between different samples. Predictive models were constructed via extreme gradient boosting, and hub genes were identified according to feature importance. Results: Blue and yellow modules were significantly related to AAA, and genes in these modules were associated with the aortic wall and immune response, respectively. In terms of aortic rupture, the most relevant module was significantly enriched in the inflammatory response. The results of GSEA and GSVA suggested that immune cells and the inflammatory response were involved in the development of AAA and aortic rupture. There were significant differences in the infiltration of immune cells and expression levels of immune-related genes among different samples. NFKB1 might be an important transcription factor mediating the inflammatory response of AAA and aortic rupture. After the construction of a predictive model, CD19, SELL, and CCR7 were selected as hub genes for AAA whereas OAS3, IFIT1, and IFI44L were identified as hub genes for aortic rupture. Conclusion: Weakening of the aortic wall and the immune response both contributed to the development of AAA, and the inflammatory response was closely associated with aortic rupture. The infiltration of immune cells was significantly different between different samples. NFKB1 might be an important transcription factor in AAA and aortic rupture. CD19, SELL, and CCR7 had potential diagnostic value for AAA. OAS3, IFIT1, and IFI44L might be predictive factors for aortic rupture.

Galectin­3 facilitates the proliferation and migration of nasopharyngeal carcinoma cells via activation of the ERK1/2 and Akt signaling pathways, and is positively correlated with the inflammatory state of nasopharyngeal carcinoma.

Nasopharyngeal carcinoma (NPC) is an epithelial carcinoma originating from the nasopharyngeal mucosal tissue and is highly prevalent in southeast Asia. Galectin­3 (gal­3) serves crucial roles in many cancers but its role in NPC remains to be elucidated. The aim of the present study was to investigate the role of gal­3 in NPC. Immunohistochemistry and ELISA were used to determine the expression level of gal­3 in patients with NPC or chronic rhinitis (CR). Gal­3 short hairpin (sh)RNA was established to knockdown gal­3 in 5­8F and 6­10B cells, allowing for the evaluation of the roles of gal­3 in proliferation, migration and apoptosis in NPC cell lines. Immunohistochemistry staining of IL­6 and IL­8 was applied to access the inflammatory state of tumor tissues, and the correlation between the inflammatory state and gal­3 was analyzed. The results demonstrated that gal­3 was upregulated in patients with NPC compared with patients with CR. Knockdown of gal­3 inhibited proliferation and migration in 5­8F and 6­10B cells, as well as promoted apoptosis in these cells. The expression levels of MMP­9 and IL­8 were also decreased in 5­8F and 6­10B cells after transfection with gal­3 shRNA. A positive correlation was identified between the expression level of gal­3 and the inflammatory state of NPC. The phosphorylation levels of ERK1/2 and Akt were downregulated after knockdown of gal­3 in 5­8F and 6­10B cells. In conclusion, the expression level of gal­3 was upregulated in patients with NPC and was positively correlated with the inflammatory state of NPC. The results suggested that gal­3 promoted the proliferation and migration of 5­8F and 6­10B cells, while inhibiting the apoptosis of these cells. Moreover, activation of ERK1/2 and Akt may be the underlying mechanism of the effects of gal­3 on NPC.

Insulin Receptor Substrate p53 Ameliorates High-Glucose-Induced Activation of NF-κB and Impaired Mobility of HUVECs.

Diabetes-related macrovascular and microvascular complications lead to poor prognosis. Insulin receptor substrate p53 (IRSp53) is known to act as a substrate for the insulin receptor tyrosine kinase, but its role in endothelial dysfunction remains unclear. Human umbilical vein endothelial cells (HUVECs) treated with D-glucose at different concentrations and a streptozocin-induced rat diabetes mellitus (DM) model were used to investigate the effects of hyperglycemia on the expression levels of IRSp53 and galectin-3 (gal-3) and the inflammatory state and mobility of HUVECs. Thereafter, IRSp53-overexpressing HUVECs and IRSp53-knockdown HUVECs were established using IRSp53-overexpressing lentivirus or IRSp53-siRNA to explore the role of IRSp53 in the HUVEC inflammatory state and HUVEC mobility. D-glucose at high concentration (HG) and hyperglycemia were found to induce downregulation of IRSp53 and upregulation of gal-3 in vitro and in vivo. Treatment with HG resulted in activation of NF-κB in HUVECs and impaired HUVEC mobility. Insulin restored HG-induced changes in the expression levels of IRSp53 and gal-3 in HUVECs and protected the cells from NF-κB activation and impaired mobility. Overexpression of IRSp53 inhibited the activation of NF-κB in HUVECs and strengthened HUVEC migration. Knockdown of IRSp53 facilitated the activation of NF-κB in HUVECs and decreased HUVEC migration. However, neither overexpression nor knockdown of IRSp53 altered the effects of insulin on HG-induced detrimental changes in HUVECs. HG and hyperglycemia resulted in downregulation of IRSp53 in vitro and in vivo. IRSp53 is concluded to inhibit the activation of NF-κB in HUVECs and to strengthen HUVEC migration.

Identification of microRNAs enriched in exosomes in human pericardial fluid of patients with atrial fibrillation based on bioinformatic analysis.

BACKGROUND: Atrial fibrillation (AF) is related to structural and electrical atria remodeling. Atrial fibrosis development and progression is characteristic of structural remodeling and is taken as the AF perpetuation substrate. Increasing evidence has confirmed that microRNAs (miRNAs) are associated with AF, including cardiac fibrosis. METHODS: Pericardial fluid (PF) samples were collected from nine adult patients who had congenital heart disease with persistent AF or sinus rhythm (SR) undergoing surgery. Abnormally expressed miRNAs were acquired, and P<0.05 and fold change >2 were taken as the thresholds of differentially expressed miRNAs (DE-miRNAs). The predicted target genes were obtained by miRTarBase. The Database for Annotation, Visualization and Integrated Discovery was used to annotate functions and analyze pathway abundance for latent targets of DE-miRNAs. STRING database was applied to construct a protein-protein interplay (PPI) network, and Cytoscape software was used to visualize the miRNA-hub gene-Kyoto Encyclopedia of Genes and Genomes (KEGG) network. DE-miRNA expressions were evaluated by quantitative polymerase chain reaction (qPCR). RESULTS: Fifty-five exosomal DE-miRNAs were found between the AF and SR samples; these included 24 miRNAs that were upregulated and 31 that were downregulated. For the top 3 downregulated miRNAs (miR-382-3p, miR-3126-5p, and miR-450a-2-3p) 283 predicted target genes were identified, and were implicated in cardiac fibrosis-related pathways, including the hypoxia-inducible factor-1 (HIF1), mitogen-activated protein kinase (MAPK), and adrenergic and insulin pathways. The top 10 hub genes in the PPI network, including mitogen-activated protein kinase 1 (MAPK1) and AKT serine/threonine kinase 1 (AKT1), were identified as hub genes. By establishing the miRNA-hub gene-KEGG network, we observed that these hub genes, which were regulated by miR-382-3p, miR-3126-5p, and miR-450a-2-3p, were involved in many KEGG pathways associated with cardiac fibrosis, such as the AKT1/glycogen synthase kinsase-3ß (GSK-3ß) and transforming growth factor-ß (TGF-ß)/MAPK1 pathways. CONCLUSIONS: The findings of the present study suggest that miR-382-3p, miR-450a-2-3p, and miR-3126-5p contained in exosomes in human PF are pivotal in the progression of AF. The results of qPCR showed that miR-382-3p was consistent with our sequencing data, which indicates its potential value as a therapeutic target for AF.

Omentin-1 is associated with atrial fibrillation in patients with cardiac valve disease.

BACKGROUND: Epicardial adipose tissue (EAT) remodeling and adipocytokines are associated with structural remodeling in atrial fibrillation (AF). However, the role of omentin-1, a novel adipocytokine, in structural remodeling remains unknown. METHODS: Hematoxylin and eosin (H&E) and Masson's trichrome stains were used to investigate the histology of EAT and right atrial appendages. The expression levels of adipocytokines in these human samples were determined by immunohistochemical assay and western blotting. Models of transforming growth factor (TGF)-ß1-induced activation of cardiac fibroblasts (CFs) and TGF-ß1-induced endothelial-mesenchymal transition (EndMT) of human umbilical vein endothelial cell (HUVEC) were established to explore roles of omentin-1 in these processes. To determine changes in adipocytokines secretion under hypoxia conditions, adipocytes were treated with 5% O2 and 95% N2, and then CFs and HUVECs were co-cultured with the conditioned medium of adipocytes to determine the effects of hypoxia-treated adipocytes on these cells. RESULTS: Expression of omentin-1 was downregulated in the EAT and right atrial appendages from patients with AF compared to samples from patients without AF, while the TGF-ß1 level was upregulated in EAT from patients with AF. EAT from patients with AF exhibited adipocyte hypertrophy and severe interstitial fibrosis. Omentin-1 inhibited TGF-ß1-induced CF activation and reversed TGF-ß1-induced HUVEC EndMT. Adipocytes treated with hypoxia exhibited downregulation of omentin-1 and partly activated CFs. CONCLUSIONS: This study demonstrated that omentin-1 was an antifibrotic adipocytokine and was downregulated in patients with AF, which was partly mediated by hypoxia.

Dimethylation of eEF1A at Lysine 55 Plays a Key Role in the Regulation of eEF1A2 on Malignant Cell Functions of Acute Myeloid Leukemia.

OBJECTIVE: This study aimed to explore whether eukaryotic translation elongation factor 1 alpha 2 affected cell proliferation, migration, and apoptosis via regulating the dimethylation of eukaryotic translation elongation factor 1 alpha at lysine 55 in acute myeloid leukemia. METHODS: The expressions of eukaryotic translation elongation factor 1 alpha 2 and dimethylation of eukaryotic translation elongation factor 1 alpha at lysine 55 in acute myeloid leukemia cell lines and human normal bone marrow mononuclear cells (as control) were assessed. Control CRISPR-Cas9 lentivirus, eukaryotic translation elongation factor 1 alpha 2 knockout CRISPR-Cas9 lentivirus, vector plasmid, eukaryotic translation elongation factor 1 alpha 2 wild type overexpression plasmid, and eukaryotic translation elongation factor 1 alpha 2 with a K55R substitution overexpression plasmid were transfected into AML-193 and Kasumi-1 cells combined or alone, and were accordingly divided into 4 groups (Sgcontrol + vector group, SgeEF1A2 + vector group, SgeEF1A2 + eEF1A2WT group, and SgeEFIA2 + eEF1A2K55R group). RESULTS: Eukaryotic translation elongation factor 1 alpha 2 and dimethylation of eukaryotic translation elongation factor 1 alpha at lysine 55 expressions were higher in AML-193, Kasumi-1, and KG-1 cell lines compared to the control. In AML-193 and Kasumi-1 cells, the knockout and compensated experiments revealed that eukaryotic translation elongation factor 1 alpha 2 promoted cell proliferation and migration but repressed apoptosis. Additionally, the knockout of eukaryotic translation elongation factor 1 alpha 2 decreased dimethylation of eukaryotic translation elongation factor 1 alpha at lysine 55 expression, meanwhile, eukaryotic translation elongation factor 1 alpha 2 wild type overexpression enhanced while eukaryotic translation elongation factor 1 alpha 2 with a K55R substitution overexpression did not influence the dimethylation of eukaryotic translation elongation factor 1 alpha at lysine 55 expression. Furthermore, eukaryotic translation elongation factor 1 alpha 2 wild type overexpression promoted cell proliferation, enhanced migration, and decreased apoptosis, but eukaryotic translation elongation factor 1 alpha 2 with a K55R substitution overexpression did not influence these cellular functions in AML-193 and Kasumi-1 cells, suggesting the implication of dimethylation of eukaryotic translation elongation factor 1 alpha at lysine 55 in eukaryotic translation elongation factor 1 alpha 2 mediated oncogenesis of acute myeloid leukemia. CONCLUSION: Eukaryotic translation elongation factor 1 alpha 2 and its dimethylated product may serve as therapeutic targets, and these findings may provide support for exploring novel strategies in acute myeloid leukemia treatment.

Omentin-1 Ameliorated Free Fatty Acid-Induced Impairment in Proliferation, Migration, and Inflammatory States of HUVECs.

OBJECTIVES: Endothelial cell injury is a critical pathological change during the development of atherosclerosis. Here, we explored the effect of omentin-1 on free fatty acid- (FFA-) induced endothelial cell injury. METHODS: An FFA-induced endothelial cell injury model was established to investigate the role of omentin-1 in this process. Cell proliferation was analyzed with the Cell Counting Kit assay and flow cytometry. Scratch and transwell assays were used to evaluate cell migration. Factors secreted by endothelial cells after injury were detected by western blotting, reverse-transcription quantitative polymerase chain reaction, and cellular fluorescence assay. RESULTS: Omentin-1 rescued the FFA-induced impaired proliferation and migration capabilities of human umbilical vein endothelial cells (HUVECs). It decreased the number of THP-1 cells attached to HUVECs in response to injury and inhibited the FFA-induced proinflammatory state of HUVECs. CONCLUSION: Omentin-1 could partly ameliorate FFA-induced endothelial cell injury.

GIAT4RA functions as a tumor suppressor in non-small cell lung cancer by counteracting Uchl3-mediated deubiquitination of LSH.

Elucidating mechanisms in tumor suppressors and epigenetic modifiers are needed to gain insights into the etiology and treatment of cancer, the interplay between long intergenic non-coding RNAs (lncRNAs) and chromatin remodeling remains unclear. Here, we showed that GIAT4RA, a poorly characterized lncRNA LOC102723729, was significantly decreased in lung cancer cells and tissues; while no association was observed with clinical risk factors, expression was linked with clinical stage and lymphatic metastasis. Higher expression of GIAT4RA was linked with overall survival in NSCLC. GIAT4RA inhibited many characteristics of tumorigenesis including cell growth, clonal formation, migration and invasion, epithelial-mesenchymal transition, tumor sphere and tumor growth in vivo. Mechanistically, GIAT4RA was essential for the degradation of chromatin modifier lymphoid-specific helicase (LSH) by counteracting the deubiquintination in proteasome pathway by binding to 227-589 AA of LSH. GIAT4RA interfered with ubiquitin hydrolase Uchl3-mediated interaction and stabilization of LSH. LSH knockdown rescued GIAT4RA-promoted features, and LSH overexpression prevented GIAT4RA-induced phenotypes. Taken together, lncRNA GIAT4RA plays a critical role in NSCLC adenocarcinoma as a ubiquitination regulator and tumor suppressor.

Metformin Inhibits the Expression of Biomarkers of Fibrosis of EPCs In Vitro.

Endothelial progenitor cells (EPCs) are a group of circulating cells with important functions in vascular repair and treatment of cardiovascular diseases. However, in patients with atrial fibrillation (AF), the number and function of EPCs reportedly are decreased. TGF-ß is highly expressed in AF patients. In this study, we examined the effect of TGF-ß1 on EPCs and the therapeutic outcome of metformin treatment on TGF-ß1-induced EPCs. EPCs were induced with TGF-ß1 at different concentrations (5 ng/ml, 10 ng/ml, and 20 ng/ml) for 48 h followed by western blot, qPCR, and immunofluorescence analyses to investigate changes in the levels of the fibrosis-related proteins, α-SMA, Col I, Col III, CTGF, and MMP-1. Live-dead cell staining was used to evaluate cell apoptosis. Compared with the control, TGF-ß1 treatment significantly (p < 0.05) enhanced the levels of α-SMA, Col I, Col III, CTGF, and MMP-1 in a dose-dependent manner. The most effective concentration of TGF-ß1 (20 ng/ml) was then used to induce fibrosis biomarker expression in EPCs, followed by treatment with metformin at different concentrations (0.5, 1, and 2 mmol/l). Metformin treatment suppressed TGF-ß-induced expression of all above factors, with the effect at 2 mmol/l being significant (p < 0.05). Live-dead cell staining showed no difference among the control, TGF-ß1-treated, and metformin-treated groups. In conclusion, our study showed that TGF-ß1 induces the expression of fibrosis biomarkers in EPCs, which is attenuated by treatment with metformin. Thus, metformin may have therapeutic potential for improving EPC function in cardiovascular diseases.

Erratum to: MiR-363 inhibits cisplatin chemoresistance of epithelial ovarian cancer by regulating snail-induced epithelial-mesenchymal transition.

The BMB Reports would like to correct in the Supplementary Figure 1 of BMB Rep. 51(9): 456-461 titled "MiR-363 inhibits cisplatin chemoresistance of epithelial ovarian cancer by regulating snail-induced epithelial-mesenchymal transition."

Endogenous reduction of miR-185 accelerates cardiac function recovery in mice following myocardial infarction via targeting of cathepsin K.

Angiogenesis is critical for re-establishing the blood supply to the surviving myocardium after myocardial infarction (MI) in patients with acute coronary syndrome (ACS). MicroRNAs are recognised as important epigenetic regulators of endothelial function. The aim of this study was to determine the roles of microRNAs in angiogenesis. Eighteen circulating microRNAs including miR-185-5p were differently expressed in plasma from patients with ACS by high-throughput RNA sequencing. The expressional levels of miR-185-5p were dramatically reduced in hearts isolated from mice following MI and cultured human umbilical vein endothelial cells (HUVECs) under hypoxia, as determined by fluorescence in situ hybridisation and quantitative RT-PCR. Evidence from computational prediction and luciferase reporter gene activity indicated that cathepsin K (CatK) mRNA is a target of miR-185-5p. In HUVECs, miR-185-5p mimics inhibited cell proliferations, migrations and tube formations under hypoxia, while miR-185-5p inhibitors performed the opposites. Further, the inhibitory effects of miR-185-5p up-regulation on cellular functions of HUVECs were abolished by CatK gene overexpression, and adenovirus-mediated CatK gene silencing ablated these enhancive effects in HUVECs under hypoxia. In vivo studies indicated that gain-function of miR-185-5p by agomir infusion down-regulated CatK gene expression, impaired angiogenesis and delayed the recovery of cardiac functions in mice following MI. These actions of miR-185-5p agonists were mirrored by in vivo knockdown of CatK in mice with MI. Endogenous reductions of miR-185-5p in endothelial cells induced by hypoxia increase CatK gene expression to promote angiogenesis and to accelerate the recovery of cardiac function in mice following MI.

MiR-363 inhibits cisplatin chemoresistance of epithelial ovarian cancer by regulating snail-induced epithelial-mesenchymal transition.

Chemoresistance is a major barrier to successful cisplatinbased chemotherapy for epithelial ovarian cancer (EOC), and emerging evidences suggest that microRNAs (miRNAs) are involved in the resistance. In this study, it was indicated that miR-363 downregulation was significantly correlated with EOC carcinogenesis and cisplatin resistance. Moreover, miR-363 overexpression could resensitise cisplatin-resistant EOC cells to cisplatin treatment both in vitro and in vivo. In addition, data revealed that EMT inducer Snail was significantly upregulated in cisplatin-resistant EOC cell lines and EOC patients and was a functional target of miR-363 in EOC cells. Furthermore, snail overexpression could significantly attenuate miR-363-suppressed cisplatin resistance of EOC cells, suggesting that miR-363-regulated cisplatin resistance is mediated by snail-induced EMT in EOC cells. Taken together, findings suggest that miR-363 may be a biomarker for predicting responsiveness to cisplatin-based chemotherapy and a potential therapeutic target in EOC. [BMB Reports 2018; 51(9): 456-461].

Activation of AhR with nuclear IKKα regulates cancer stem-like properties in the occurrence of radioresistance.

Most cancer patients receive radiotherapy in the course of their disease and the occurrence of radioresistance is associated with poor prognosis. The molecular pathways that drive enhanced tumorigenic potential during the development of radioresistance are poorly understood. Here, we demonstrate that aryl hydrocarbon receptor (AhR) plays a vital role in the maintenance of cancer stem-like properties. AhR promotes the cancer stem-like phenotype and drives metastasis by directly targeting the promoters of 'stemness' genes, such as the ATP-binding cassette sub-family G member 2 (ABCG2) gene. Moreover, the radioresistant sublines display high levels of oncometabolites including α-ketoglutarate, and treatment of cancer cells with α-ketoglutarate enhances their stem-like properties in an AhR activation-dependent manner. IKKα directly activates stemness-related genes through an interaction with AhR as a bone fide chromatin modifier. Thus, AhR is functionally linked with cancer stem-like properties, and it drives tumorigenesis in the occurrence of radioresistance.

High glucose forces a positive feedback loop connecting ErbB4 expression and mTOR/S6K pathway to aggravate the formation of tau hyperphosphorylation in differentiated SH-SY5Y cells.

High glucose (HG)-induced mammalian target of rapamycin (mTOR) overactivation acts as a signaling hub for the formation of tau hyperphosphorylation, which contributes to the development of diabetes-associated cognitive deficit. How HG induces the sustained activation of mTOR in neurons is not clearly understood. ErbB4, a member of the receptor tyrosine kinase family, plays critical roles in development and function of neural circuitry, relevant to behavioral deficits. Here, we showed HG-induced ErbB4 overexpression in differentiated SH-SY5Y cells and primary hippocampal neurons and hippocampal pyramidal neurons of streptozotocin-induced diabetic rats. Inhibition of ErbB4 signaling prevented the HG-induced activation of mTOR/S6K signaling to suppress tau hyperphosphorylation. In contrast, ErbB4 overexpression increased the activation of mTOR/S6K signaling, resulting in tau hyperphosphorylation similar to HG treatment. We also demonstrated that HG upregulated the expression of ErbB4 at a mTOR-dependent posttranscriptional level. Together, our results provide the first evidence for the presence of a positive feedback loop for the sustained activation of mTOR involving overexpressed ErbB4, leading to the formation of tau hyperphosphorylation under HG condition. Therefore, ErbB4 is a potential therapeutic target for diabetes-associated neurodegeneration.